The reductive conversion of ribonucleotides to deoxyribonucleotides, catalyzed by ribonucleotide reductase, is a crucial and rate-limiting reaction in the DNA biosynthetic pathway. This reaction, therefore, represents a logical target for cancer chemotherapy. In response to the need for an effective agent at this site, a series of ribonucleotide reductase inhibitors, based on a vicinal polyhydroxyphenyl structure, have been developed. The compound of the initial series with the best antitumor activity in animal tumor models, Didox, has entered human clinical trials. The purpose of this proposal is to enhance the therapeutic efficacy of the anticancer drugs, Didox and Amidox, by conjugating them to a biocompatible polymer. It is hope that the drug- polymer conjugate will reduce the rate of Didox metabolism and elimination in order to achieve a longer biological half life. Initial human clinical pharmacokinetic studies indicate that Didox has a short half life in the plasma. During the phase I period, we will prepare Didox and Amidox and biocompatible polymer and attach the drug directly to the polymer or through a degradable spacer group. The drug-polymer adducts will be characterized and studies will be performed to determine whether they inhibit mammalian ribonucleotide reductase before and after treatment with microsomal and lysosomal enzymes. The cytotoxic effects of drug-conjugates against tissue culture cells will be ascertained. Most importantly, the antitumor activity of the drug-polymer conjugates in the L1210 leukemia and Lewis lung tumor models will be determined.